From analyzing M&Ms to illuminating cells

MIT biophysicist Ibrahim Cissé shares the story of his research career

Ibrahim Cissé hopes his research will shed light on processes that take place within living cells, such as protein aggregation.
Courtesy of MIT Department of Physics

Ibrahim Cissé,Assistant Professor of Physics and principal investigator of Cissé Laboratory, has been interested in science for as long as he can remember — he was "very curious as a child, wanted to find out how things worked," and loved watching scientific Hollywood movies. As a young boy, he converted a storage room in his house into a laboratory, where he would tinker with electronics, taking things apart to build creations of his own.

Still, he never considered science as a possible career option. Growing up in Niger, science was not something he thought he could pursue. In fact, he expected to follow in his father's footsteps by becoming a lawyer. However, it was his long-cherished dream of coming to the United States that made it possible for him to study science.

Self-confessedly “very much into the pop culture at the time,” Cissé was eager to come to the U.S., where “all the cool stuff was happening.” He finished high school two years early by self-studying for and passing the National Baccalaureate exam as an independent candidate. Although the exam had no age restriction, he was nervous that his youth would draw questions, and recalls persuading his older brother to submit the application form for him.

Cissé’s parents always encouraged him to pursue his interests — they happily surrendered their storage room and supported his drive to independently study for his exam. With the exam’s low pass rate, however, they worried he wasn’t mentally prepared for the possibility of failure. Assuring them that he wouldn’t lose heart if his plans didn’t work out, Cissé extracted a promise that they would let him study in the U.S if he passed. Soon enough, he cleared the exam on his first attempt and held them to their word.

Cissé had his first experience with research as an undergraduate at North Carolina Central University, studying the random packing of ellipsoids and determining how many contacts each ellipsoid made with its neighbours.

“It was actually experimental — we took M&M candies, poured the M&Ms in a jar, and tried to figure out how the geometry of the objects could help us understand the random packing density. We tried sophisticated approaches, like going to the local hospital and doing an MRI scan on the jar. To reconstruct it, you had all this computational need, and if you missed even a few M&Ms on the scan, it became tedious.”

In the end, Cissé came up with a simple yet ingenious solution, “the type of thing one would come up with if you were a kid and you had your own lab.” He poured thin paint into the jar of M&Ms, drained the paint, and counted the unpainted spots on each one to conclude that they made, on average, 10 contacts with their neighbours.

“I presented it to my professor, and he said, ‘I don’t believe it, I want to see it.’ When I showed him the M&Ms covered in paint, he told me, ‘You don’t know what this means.’ Although it was serendipitous for me, this was a problem that people had been trying to solve for some time. That was my first publication.”

Cissé credits his PhD supervisor from the University of Illinois at Urbana-Champaign, Taekjip Ha, for introducing him to the field of single molecule bioimaging. Ha’s research coupled distance-dependent intermolecular interactions to fluorescent beacons on the biomolecules, creating a “ruler to probe interactions within a few nanometers.”

“I emailed him and I said, ‘I'm very fascinated by what I read on your website. Could I just come for the summer before grad school and try it out?’ I went there that summer, and I never looked back. What's fascinating is that instead of looking at molecules in a test tube at the Avogadro number level, you can look at single molecules one at a time. Once I finished my PhD, I thought, rather than purifying the molecules outside cells, can we bring the microscopy inside cells?”

Cissé developed a technique to observe the movements of groups of biomolecules within a cell over time. “We put the molecules primarily in an off state, and give them a low probability of turning on. But if you do a small illumination, of very low power, a few of them will stochastically turn on, and start emitting another wavelength. And you control the emission intensity to make the molecule blink.” By controlling groups of molecules before they can reach the ‘on’ state, he has been able to track their movements in super-resolution.

He has since used it to discover that RNA polymerase enzymes condense into short-lived clusters that seldom last for longer than eight seconds — far too short to carry out their function of producing messenger RNA, a process that takes several minutes.The clusters are made up of 80-100 RNA polymerases, which clump around gene loci during DNA transcription.

Prior to his discovery, scientists had believed that RNA polymerases were not involved in regulating gene expression — but in 2016, Cissé found evidence to prove otherwise.

“The clusters’ lifespans were correlated with how many messenger RNAs [were produced].” He and his team soon found out that the clustering took place in order to load the polymerases on the DNA — a process that only needed a few seconds, after which they could “take their time” to produce messenger RNA. “The longer the cluster stays, the more polymerase can be loaded and more RNA comes out.”

Today, his research group continues to work toward understanding how the clusters are formed and characterizing their physical properties. Cissé hopes his research will shed light on processes that take place within living cells and believes it can be applied to the diagnosis of neurodegenerative diseases such as ALS and Parkinson's Disease, which are characterized by protein aggregates that condense together like the RNA polymerase clusters. Cissé envisions a day when super-resolution microscopy will be able to detect these clusters long before brain imaging can, allowing patients to be diagnosed and treated early.